Leukocytosis (includes leukaemia) Flashcards
Typical ages of leukaemia presentations?
- ALL: children and older adults
- CML: 40 - 60y
- AML, CLL: >60y
Leukemia v lymphoma?
-Leukemia: malignant cells arise in bone marrow and may spread elsewhere (inc blood and bone marrow).
-Lymphoma: malignant cells arise in lymph nodes/tissues and may spread elsewhere (inc blood and bone marrow).
Location where malignant cells are found does not solely define malignancy: classified on cell characteristics.
What is AML?
Rapidly progressive malignancy characterised by failure of myeloid cells to differentiate beyond blast stage.
Epidemiology AML?
- Incidence inc w/ age (median onset = 65y)
- 10-15% childhood leukemias
RFx AML?
- myelodysplastic syndromes
- benzene
- radiation
- alkylating agents as treatment for previous malignancy
- Infections e.g. adult T cell leukaemia lymphoma and HTLV1
- Genetics e.g. trisomy 21, high risk AML
- Rare familial syndromes (e.g. Fanconi’s anemia)
What does uncontrolled progression of blasts in marrow lead to?
- suppression of normal haematopoietic stem cells
- appearance of blasts in peripheral blood
- accumulation of blasts in other sites (skin, gums)
- metabolic consequences; tumour lysis syndrome
Blood alterations in AML?
- Anemia
- Thrombocytopenia
- Neutropenia (even w/ normal WBC)
What causes skeletal pain and bony tenderness in AML?
Accumulation of blast cells in marrow
What is leukostasis / hyperleukosis syndrome?
Medical emergency.
Large numbers of blasts interfere with circulation and lead to hypoxia and haemorrhage - can cause diffuse pulmonary infiltrates, CNS bleeding, resp distress, altered mental state, priapism.
What are the metabolic effects of AML?
- Increased uric acid -> nephropathy, gout
- Release of phosphate -> decreased Ca2+, decreased Mg2+
- Release of procoagulants -> DIC
Why is PO4(3-) increased in AML?
PO4(3-) is released by leukaemia blasts.
Bloods in AML?
- FBE: anemia, thrombocytopenia, variable WBC
- INR / aPTT
- Fibrin degradation products / fibrinogen (in DIC)
- Increased LDH
- Increased uric acid
- CMP: Increased PO4 (3-), Decreased Ca2+
- Peripheral blood film
Findings on peripheral blood film in AML?
- Circulating blasts with Auer rods (azurophilic granules) ==> pathognomonic for AML.
- Changes to multiple lineages typical esp cytopenias resulting from suppression of normal haematopoiesis.
Bone marrow aspirate findings in AML?
-Blast count >20% (N =
Other Ix in AML work up? (non blood, non BMA)
- CXR: r/o pneumonia
- ECG
- MUGA scan (pre chemo; cardiotoxic)
AML treatment strategy?
- Induction: induce complete remission of AML
Check BMA response - Consolidation: prevent recurrence e.g. intensive consolidation chemotherapy, stem cell transplantation
Supportive care in AML treatment?
- Screen for infection: Regular MCS of all sites possible
- Fever: MCS all sites, CXR, ABx
- Platelet and RBC transfusions
- prevent metabolic abnormalities (eg. allopurinol)
Acute v chronic wrt leukemia?
Characterises the clinical presentation and response to therapy of the condition.
Clinical presentation of acute leukaemia?
-Anemia: lethargy, dyspnoea, pallor, presyncope
-Neutropenia: FCR, infections
-Thrombcytopenia: bruising, bleeding
-B symptoms: fevers, sweats, weight loss
-Organ infiltration
Rarer: lymphadenopathy, hepatosplenomegaly, symptoms of hyperleukocytosis
What is immunophenotyping?
Intensity with which a fluorescence-conjugated Ab stains cell surface proteins: if strong staining, cell surface protein present.
What is the first lab test in leukaemia work up?
Immunophenotyping using flow cytometry:
-determines pattern of acute leukaemia through surface antigen expression i.e. AML v ALL stain for myeloid vs lymphoid markers
What is another use for flow cytometry immunophenotyping beyond determining pattern of leukaemia?
- Identifying aberrant expression (80% acute leukemias).
e. g AML blasts may express a lymphoid antigen.
What are the cytogenetic risk groups in AML?
Used to inform prognosis.
- GOOD: t(8;21), inv 16, t(15;17)
- INTMED: mostly normal cytogenetics
- POOR: monosomy 7, multiple complex abnormalities, chr 3 abnormalities.
What is the role of molecular testing in AML?
- Defining mutations with prognostic significance
- Diagnosing specific translocations to confirm cytogenetic findings
- Quantifying transcript to monitor treatment response
How is prognosis determined in AML?
AT Dx: cytogenetics, molecular findings
DURING Rx:
-flow cytometric evidence of residual disease
-disappearance of previous cytogenetic abnormalities
How is response to therapy monitored in acute leukaemia?
- BMA and trephine:
Main chemotherapy induction drugs?
Cytarabine
+
an anthracycline e.g. idarubicin (cardiotoxic)
Specific additions to standard therapy in ALL treatment?
- Maintenance therapy post consolidation: 2-3y to prevent relapse
- Multi drug Rx e.g. L-asparaginase
- Intrathecal chemo due to RR CNS relapse
What is APML?
Acute promyelocytic leukemia: ass/w t(15:17) ==> forms PML/RARa.
New therapies: now one of most curable leukemias!!
What is the major feature of APML presentation?
Bruising and bleeding
Coagulation study results in APML?
DIC with low fibrinogen (due to release of pro-coagulants from malignant promyelocytes)
APML morphological characteristics?
Faggot cells containing many Auer rods.
Cytogenetics of APML?
t(15;17): translocation of retinoic acid receptor (RARa) on 17 w/ promyelocytic leukemia gene (PML) on 15 ==> PML-RARa.
Mx APML?
- Correct coagulopathy: platelets, cryoprecipitate and fibrinogen as needed
- All trans retinoid acid (ATRA) induces promyelocyte differentiation.
- arsenic
Epidemiology ALL?
-75%
What is ALL?
Malignant disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal haematopoietic cells of the bone marrow.
How is ALL subdivided?
Cell of origin (B or T)
Symptoms of organ infiltration in leukemias?
- Gingivial hypertrophy (may present to dentist!)
- Hepatosplenomegaly (ALL)
- Lymphadenopathy
- Skin: leukemia cutis
- Gonads (ALL)
- Eyes: Roth spots, cotton wool spots, vision changes
How can leukemia symptoms be rationalised / categorised?
Categorised as due to:
- Bone marrow failure: anaemia, thrombocytopenia, neutropenia
- Organ infiltration: tender bones, lymphadenopathy, hepatosplenomegaly, meningeal signs.
ALL good prognostic factors?
- Young
- WBC
Prognosis ALL?
-Kids 80% long term remission
Adults only 30-40% 5y survival
Cytogenetic indicators of ALL prognosis?
POOR: t(4;11)
GOOD: t(9;22) now good with tyrosine kinase inhibitor therapy
How is need for allogeneic marrow transplant determined?
-Age (
What is CML?
Myeloproliferative disorders characterised by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate.
Epidemiology CML?
Any age group. Median age 65y
Pathophysiology CML?
Ph Chr = t(9;22) forming bcr-abl fusion gene, an active tyrosine kinase.
What are the 3 phases of CML?
- Chronic Phase (85% pts)
- Accelerated Phase
- Blast Crisis
What is the chronic phase of CML?
-Few blasts (
What is the accelerated phase of CML?
Impaired neutrophil differentiation
- circulating blasts (10-19%) w/ increased peripheral basophils (pruritus)
- FBE: thrombocytopenia
- worsening constitutional symptoms
- splenomegaly (extramedullary haematopoiesis)
What is the blast crisis phase of CML?
Aggressive course: blasts fail to differentiate.
- blasts (>20%) in peripheral blood or marrow
- reflects acute leukemia
Clinical presentation CML?
Many pts asymptomatic / non-specific Sx
-2” Splenic involvement:early satiety, shoulder tip pain, splenomegaly
Peripheral blood film features CML?
-Leukoerythroblastic picture: immature RBCs and granulocytes present e.g. myelocytes and normoblasts
BMA features in CML?
- Myeloid hyperplasia with left shift
- increased megakaryocytes
- mild fibrosis
Symptomatic treatment CML?
Allopurinol and antihistamines
Chronic phase treatment CML?
Imatinib (Gleevec): tyrosine kinase inhibitor in bcr-abl cells ==> inhibits proliferation and induces apoptosis.
If loss of response, trial 2nd/3rd generation inhibitors.
Treatment accelerated / blast phase CML?
- Refer for clinical trial 2nd/3rd gen TKIs
- Prepare for allogeneic stem cell transplant
How is treatment success determined in CML?
Therapeutic miletones:
- Haem: improved WBC and plt counts, reduced basophils
- Cytogenetic: undetectable Ph-Chr in bone marrow
- Molecular: reduced / absent bcr-abl in periphery and marrow
Prognosis acute phase CML?
- 2/3 develop AML picture (unresponsive to remission induction)
- 1/3 develop ALL picture
Ix in CML?
- FBE: leukocytosis w/ early myeloid cells, basophils, eosinophilia
- BMA: hypercellular
- Cytogenetics: t(9;22)
- Molecular: bcr-abl
CML response monitoring post therapy?
PCR monitoring of bcr-abl transcript in peripheral blood every 3/12 aiming for major molecular response (MMR) =
What are the second generation TKIs used when imatinib no longer effective?
Dasatinib
Nilotinib
What is CLL?
Indolent disease characterised by clonal malignancy of mature B cells.
Epidemiology of CLL?
- most common leukemia
- mainly older puts; median 65y
- M>F
Pathophysiology of CLL?
Accumulation of neoplastic lymphocytes in blood, bone marrow, LNs and spleen
What are the features of immune dysregulation due to CLL?
- ITP
- AI haemolytic anemia
- Hypogammaglobulinemia
- +/- neutropenia
What are smudge cells?
Artifacts of damaged lymphocytes from slide preparation
Ix in ?CLL?
- FBE: aboslute lymphocytes >5x10^9 w/ a CLL phenotype
- Film: lymphocytes small and mature, smudge/smear cells
- Flow cytometry
- Cytogenetics: FISH
- BMA: lymphocytes >30%
- CT: staging
Natural history CLL?
Indolent but incurable; slow progression.
Treatment CLL?
Based on symptoms symptoms:
-observation if asymptomatic
-fludarabine + cyclophosphamide + rituximab
-corticosteroids, IVIG for ai phenomena
Allograft only curative; majority ineligible.
How is CLL prognosis determined?
Rai staging. Risk =
- LOW: lymphocytes blood and marrow only
- MID: lymphocytosis with enlarged nodes in any site / hepatosplenomegaly
- HIGH: lymphocytosis with disease related anaemia or thrombocytopenia
Complications of CLL?
- Bone marrow failure
- immune complications (AIHA, ITP, immune deficiency)
- gammopathy
- hyperuricemia w/ Rx
- 5% undergo Richter’s transformation
What is Richter’s transformation?
Aggressive transformation of CLL to diffuse large B-cell lymphoma.
Immunophenotype CLL?
-Immunophenotype: B lymphocytes co expressing CD5 (not normal) and CD-19/-23.
Cytogenetics in CLL? How can inform prognosis?
FISH.
- Indolent course: del 13q
- Aggressive course: del 17p (w/ loss of p53)
